Prevention of vascular graft occlusion and thrombus-associated thrombin generation by inhibition of factor XI
Prevention of vascular graft occlusion and thrombus-associated thrombin generation by inhibition of factor XI
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DOI：
10.1182/blood-2008-06-163675
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发表时间：
2009-01-22
期刊：
影响因子：
20.3
通讯作者：
Hanson, Stephen R.
中科院分区：
文献类型：
--
作者：
Tucker, Erik I.;Marzec, Ulla M.;Hanson, Stephen R.
凝血酶是正常止血和病理性血栓形成所必需的。由于凝血因子XI （FXI）依赖性血栓生长的机制尚不清楚，我们在灵长类血栓形成模型中研究了FXI对血栓形成的贡献。用一种新型抗人FXI单克隆抗体（aXIMab; 2 mg/kg）预处理狒狒，在10天内抑制血浆FXI至少99%，并抑制凝血酶-抗凝血酶（TAT）复合物和β -血栓球蛋白（β - TG）的形成，后者是在胶原包被血管移植物血栓形成的下游测量到的。aXIMab抑制FXI抑制了4毫米直径移植物中的血小板和纤维蛋白沉积，而没有明显增加血栓中d -二聚体的释放，并且在不影响模板出血次数的情况下防止了2毫米直径移植物的闭塞。相比之下，阿司匹林（32 mg/kg）预处理延长了出血时间，但未能防止移植物闭塞，这支持了FXI阻断在出血并发症方面可能比其他抗血栓药物具有治疗优势的概念。在全血中，aXIMab可阻止独立于因子XII和因子VII的胶原包被流腔中的纤维蛋白形成。这些数据表明，内源性FXI通过显著扩增血栓管腔表面的凝血酶生成，促进了动脉血栓的传播。(血。2009;113:936 - 944)
The protease thrombin is required for normal hemostasis and pathologic thrombogenesis. Since the mechanism of coagulation factor XI (FXI)-dependent thrombus growth remains unclear, we investigated the contribution of FXI to thrombus formation in a primate thrombosis model. Pretreatment of baboons with a novel anti-human FXI monoclonal antibody (aXIMab; 2 mg/kg) inhibited plasma FXI by at least 99% for 10 days, and suppressed thrombin-antithrombin (TAT) complex and beta-thromboglobulin (beta TG) formation measured immediately downstream from thrombi forming within collagen-coated vascular grafts. FXI inhibition with aXIMab limited platelet and fibrin deposition in 4-mm diameter grafts without an apparent increase in D-dimer release from thrombi, and prevented the occlusion of 2-mm diameter grafts without affecting template bleeding times. In comparison, pretreatment with aspirin (32 mg/kg) prolonged bleeding times but failed to prevent graft occlusion, supporting the concept that FXI blockade may offer therapeutic advantages over other antithrombotic agents in terms of bleeding complications. In whole blood, aXIMab prevented fibrin formation in a collagen-coated flow chamber, independent of factor XII and factor VII. These data suggest that endogenous FXI contributes to arterial thrombus propagation through a striking amplification of thrombin generation at the thrombus luminal surface. (Blood. 2009;113:936-944)